Progesterone is a primary progestational substance produced by ovarian cells of the corpus luteum. Progestins, e.g., progesterone and its derivatives, transform the proliferative endometrium into secretory endometrium. This change in the endometrium is essential to the implantation of a fertilized ovum and the development of a placenta during conception and the early stages of pregnancy. Many of these changes require, however, the presence of estrogen. Therefore, in the absence of estrogen, progestins can exert an atrophic effect on the endometrium, as well as various other contraceptive effects. Such contraceptive effects may vary depending on the concentration and the nature of the particular progestin involved.
Accordingly, various progestins have been utilized as contraceptive drugs due to their convenient nature coupled with their fairly predictable ovulatory and progestational effects. One specific progestin that has received much attention is norethindrone (NE) and its prodrug norethindrone acetate (NEA). Both compounds have been orally and transdermally administered as part of a number of specific formulations. Though the actions of these and other progestins can vary, many exert effects on the ovaries, the endometrium, and the cervix. For example, certain long-acting injectable progestins in appropriate doses can cause endometrial atrophy. Oral preparations can vary according to the drug and the dose, some permitting a normal endometrium and others causing regression. Progestins can also inhibit ovulation by suppressing the ovarian response to gonadotropins. This may cause a failure to ovulate or, if ovulation does occur, a smaller hyposecreting corpus luteum. Particularly high doses of progestins tend to suppress the pituitary release of lutenizing hormone and the hypothalamic release of gonadotropin releasing hormone (GnRH), which can act to prevent ovulation through decreased gonadotropin output. Progestins also tend to increase the viscosity of cervical mucous secretions and therefore impede the mobility of sperm. These and other actions of progestins can act in combination to provide effective contraception.
One undesirable issue with the use of oral progestin-only contraception is the need for consistent dosing at the same time each day. The onset of cervical mucus thickening typically occurs within about 2 hours of dosing and lasts for about 16 to 19 hours. By about 24 hours post dose, the cervical mucus returns to substantially normal viscosity. Since thickening of cervical mucus is such an important factor in attaining the progestin-induced contraceptive effect, it is extremely important that dosing take place substantially 24 hours apart in order to maintain the elevated mucus viscosity. Of course, such a stringent dosing regimen is inconvenient and runs a high risk of non-compliance.
Additionally, progestin-only contraception tends to induce certain adverse side effects. One of the most inconvenient of such side effects is spotting and breakthrough bleeding. Such bleeding can be unpredictable or irregular in onset, and in some cases bleeding can be more voluminous than in regular menstruation. Such effects can often weigh heavily against the supposed convenience of this form of birth control.
Therefore, formulations and methods for progestin-only contraception which minimize the incidence of adverse side effects, particularly spotting and breakthrough bleeding, continue to be sought.